The goal of this work is to use the high-precision tools of bioengineering to help unravel one of the deep questions of modern psychiatry: what is the neural basis of emotion? While many brain regions and neuromodulators have been implicated in emotional processing, a clear picture of the neurophysiological regulation of mood has been elusive. Precise knowledge of this physiology, on the spatial and temporal scales relevant for neural information processing, would drastically improve our ability to design and implement novel therapeutic strategies and could thereby revolutionize psychiatric practice. Of the several brain regions implicated in mood regulation, the hippocampus is hypothesized to play a particularly strong role. To gain insight into the role of the hippocampus in mood regulation, development is underway of emergent high resolution optical technologies that enable recording and stimulation of neural activity on the relevant spatial and temporal scales. By utilizing animal models displaying behavioral correlates of mood, manipulating this behavior bidirectionally with antidepressants and stress paradigms, and then assaying effects of these behavioral modifications with the forced swim test, this proposal seeks to investigate three specific aims pertinent to this question: 1) Identify spatiotemporal patterns of evoked hippocampal activity that are affected by bidirectional modulation of forced swim test performance, and resolve whether these activity patterns correlate well with animal behavioral state. 2) Determine the sufficiency of these projections to modulate forced swim test performance via in vivo stimulation of applicant pathways identified using high-speed imaging. 3) Isolate neuronal populations that are primary in the role of these hippocampal projections in regulating forced swim test performance. Depression affects over 121 million people worldwide and frontline treatments show limited efficacy and the potential for developing serious side effects. This work will have great impact on public health as it will identify and quantitatively describe key components of the neural mood regulatory machinery. As neural stimulation techniques have already demonstrated efficacy in relieving depression, the proposed research may lead directly to discovering additional targets for such treatment as it contributes to the formation of a quantitative theory of mood and depression.